CN112516121B - Composition containing taurine and allopurinol and medical application thereof - Google Patents

Abstract

The invention provides a composition which comprises taurine and allopurinol as main components, wherein the content ratio of the taurine to the allopurinol is 20:1 to 1:1 in terms of mass ratio. The composition can be used for preventing or treating hyperuricemia or hyperuricemia complications.

Description

Composition containing taurine and allopurinol and medical application thereof

Technical Field

The present invention relates to a composition comprising taurine and allopurinol, and in particular, the composition can be used for preventing or treating hyperuricemia or a complication of hyperuricemia.

Background

Uric acid is the terminal metabolite of human purine compounds. Disorders of purine metabolism lead to Hyperuricemia (HUA). Hyperuricemia is caused by excessive production and/or insufficient excretion of uric acid in the body, and can be divided into primary hyperuricemia and secondary hyperuricemia. Hyperuricemia was defined clinically as having serum uric acid in men above 420. mu. mol/L (7.0mg/dL) and in women above 350. mu. mol/L (5.8 mg/dL).

Epidemic disease survey shows that the incidence rate of hyperuricemia in China is 13%, wherein male accounts for about 18%, female accounts for about 8%, the total population of the patient reaches 1.8 hundred million, and the disease becomes the fourth highest after hypertension, hyperlipidemia and hyperglycemia.

Simple hyperuricemia is not a fatal disease, and most patients do not have subjective symptoms. However, if the blood uric acid is kept in a high level state for a long period of time, complications such as gout, renal failure, hypertension, cardiovascular diseases, and the like may be caused. The research results show that the total mortality and the cardiovascular disease mortality are respectively increased by 8 percent and 12 percent when the serum uric acid level is increased by 1 mg/dL. European diagnosis and treatment expert consensus of hyperuricemia and high cardiovascular disease risk patients in 2018 has listed hyperuricemia as an independent risk factor of cardiovascular diseases. In addition to gout, which severely affects quality of life, the primary goal of clinical control of uric acid is to control fatal diseases caused by uric acid, particularly cardiovascular diseases. Many clinical trials indicate that uric acid is closely related to atherosclerosis and may be the main cause of uric acid-induced cardiovascular diseases.

Clinically, allopurinol or febuxostat and other xanthine oxidase inhibitors are generally adopted to reduce the formation of uric acid, but large-scale clinical test results show that although the xanthine oxidase inhibitors achieve a certain effect of controlling uric acid, the effects of atherosclerosis are not improved, the incidence rate of myocardial infarction, stroke, heart failure and other cardiovascular diseases is not reduced, and the clinical treatment target is not achieved.

Currently, effective drugs against atherosclerosis caused by hyperuricemia are lacking.

Disclosure of Invention

The purpose of the present invention is to provide a pharmaceutical composition which is effective for preventing or treating hyperuricemia or a complication of hyperuricemia, particularly atherosclerosis.

Specifically, the present invention provides:

1. a composition comprises taurine and allopurinol as main components, wherein the content ratio of the taurine to the allopurinol is 20:1 to 1:1 by mass ratio.

2. The composition according to item 1 above, wherein the content ratio of taurine to allopurinol is 16:1 to 10:1 by mass ratio.

3. A pharmaceutical composition comprises taurine and allopurinol as main components, and pharmaceutically acceptable additives, wherein the content ratio of taurine to allopurinol is 20:1 to 1:1 by mass ratio.

4. The pharmaceutical composition according to item 3 above, wherein the content ratio of taurine to allopurinol is 16:1 to 10:1 by mass ratio.

5. The pharmaceutical composition according to item 3 or 4 above, which is used in the form of any one of tablets, pills, capsules and granules.

6. Use of the composition according to item 1 above for the manufacture of a medicament for preventing or treating hyperuricemia or a complication of hyperuricemia.

7. The use of item 6 above, wherein the complication of hyperuricemia comprises atherosclerosis.

ADVANTAGEOUS EFFECTS OF INVENTION

The composition according to the present invention is effective for preventing or treating hyperuricemia or a complication of hyperuricemia, particularly atherosclerosis, and thus is expected to be a candidate drug for treating hyperuricemia or a complication of hyperuricemia.

Detailed Description

The present invention is described in detail below by way of the description of the specific embodiments, but this is not a limitation of the present invention, and various modifications or improvements can be made by those skilled in the art according to the basic idea of the present invention, but they are within the scope of the present invention as long as they do not depart from the basic idea of the present invention.

Taurine (Taurine) is a sulfur-containing amino acid with the chemical name of 2-aminoethanesulfonic acid and the molecular formula of C₂H₇NO₃S, the molecular weight is 125.15, and the structural formula is shown in the following chemical formula 1.

[ chemical formula 1]

Taurine is one of the most abundant free amino acids in mammalian tissues. As a medicine, taurine has been widely used in China, has the effects of resisting inflammation, relieving fever, easing pain, calming, reducing blood pressure, reducing blood sugar, resisting arrhythmia, resisting bacteria, resisting platelet aggregation, enhancing immunity, benefiting gallbladder, strengthening liver, detoxifying, regulating vascular tension and the like, and has multiple clinical applications: for example, it can be used for treating acute and chronic hepatitis, fatty liver, cholecystitis, bronchitis, tonsillitis, acute conjunctivitis, herpetic conjunctivitis, and viral conjunctivitis; it can also be used for treating common cold, fever, epilepsy, infantile spasm, heart failure, arrhythmia, hypertension, metrorrhagia, arteriosclerosis, acne, etc. Taurine is also used as a food additive for various functional health foods.

In the present invention, taurine may be a commercially available product, for example, a product sold by Sigma Aldrich trade company, Inc. (product name: Sigma-Aldrich taurine 107-35-7).

Allopurinol (Allopurinol) is also called Allopurinol, and the name of the Allopurinol is 4-hydroxypyrazolopyrimidine, and the structural formula of the Allopurinol is shown in the following chemical formula 2.

[ chemical formula 2]

Allopurinol is a marketed drug for inhibiting the production of uric acid, belongs to a xanthine oxidase inhibitor, and can inhibit xanthine oxidase, so that hypoxanthine and xanthine cannot be converted into uric acid, namely, the synthesis of uric acid is reduced, the concentration of uric acid in blood is further reduced, the deposition of urate on bones, joints and kidneys is reduced, and the synthesis of uric acid is inhibited. Currently, there are mainly tablet and sustained release capsule formulations on the market, clinically used for: 1. primary and secondary hyperuricemia, especially hyperuricemia with overproduction of uric acid, also for renal insufficiency; 2. can be used for treating gout, and is suitable for patients with recurrent or chronic gout. Can be used for treating gouty nephropathy, and can relieve symptoms and reduce formation of uric acid calculus in kidney; 3. tophus; 4. can be used for treating uric acid renal calculus and/or uric acid nephropathy.

In the present invention, as the Allopurinol raw material, a commercially available product, for example, a product sold by Sigma Aldrich trade company, Inc. (product name: Sigma-Aldrich A8003 metabolite Allopurinol) can be used.

In addition to the taurine and allopurinol monomers, their salts may also be used separately. The salts may be pharmaceutically acceptable salts. Specifically, there may be mentioned: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, etc.; salts with metal cations such as sodium, potassium, magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, and ethanolamine, salts with various amino acids and amino acid derivatives such as acetylleucine, lysine, and ornithine, or ammonium salts.

A first aspect of the present invention relates to a composition comprising taurine and allopurinol as main components. The "main component" means a component having a content of 90% by mass or more of the total mass of the composition, preferably 95% by mass or more of the total mass of the composition, and more preferably 99% by mass or more of the total mass of the composition.

In the composition, the content ratio of taurine to allopurinol is 20:1 to 1:1, preferably 16:1 to 5:1, more preferably 16:1 to 10:1, and further preferably 15:1 to 12:1, in terms of mass ratio. When the ratio of the content of taurine to allopurinol is within the above range, hyperuricemia or a complication of hyperuricemia can be effectively prevented or treated.

A second aspect of the present invention relates to a pharmaceutical composition comprising taurine and allopurinol as main components, and a pharmaceutically acceptable additive.

In the pharmaceutical composition, the content ratio of taurine to allopurinol is 20:1 to 1:1, preferably 16:1 to 5:1, more preferably 16:1 to 10:1, and further preferably 15:1 to 12:1, in terms of mass ratio. When the ratio of the content of taurine to allopurinol is within the above range, hyperuricemia or a complication of hyperuricemia can be effectively prevented or treated.

In the above pharmaceutical composition, taurine and allopurinol are mixed with pharmaceutically acceptable additives to obtain a pharmaceutical composition that can be orally or parenterally administered. The pharmaceutical compositions may be formulated by conventional methods.

Administration can be carried out in a form of oral administration (for example, tablets, pills, capsules, granules, powders, liquid preparations, etc.) or in a form of parenteral administration (for example, injections, suppositories, eye drops, eye ointments, liquid preparations for percutaneous absorption, ointments, patches for percutaneous absorption, liquid preparations for transmucosal absorption, patches for transmucosal absorption, inhalants, etc. in the case of intraarticular, intravenous, intramuscular, etc.).

As the solid composition for oral administration, tablets, powders, granules, capsules and the like can be used. In such solid compositions, taurine and allopurinol are mixed with at least one additive. The additives include excipient, disintegrant, lubricant, etc.

Excipients include, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and/or magnesium aluminum silicate, and the like.

Disintegrants include cellulose (e.g., calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium or crystalline cellulose), starches (e.g., corn starch, pregelatinized starch or sodium carboxymethyl starch), crospovidone, and the like.

The lubricant comprises magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, talc, polyethylene glycol, etc.

The solid preparation of the present invention may optionally contain appropriate amounts of other additives according to the purpose. These additives include binders, plasticizers, coating agents, deflocculants, solubilizers, sweeteners, acidulants, flavorants, pH adjusters, co-solvents, colorants, flavorants, and the like. The binder includes sodium alginate, gelatin, dextrin, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, etc. The plasticizer comprises triethyl citrate, glycerin fatty acid ester, polyethylene glycol, etc. The coating agent comprises ethyl cellulose, hydroxypropyl methyl cellulose, etc. Deflocculants include talc, calcium stearate, and the like. The solubilizer comprises sucrose fatty acid ester, sorbitan monostearate, sodium dodecyl sulfate, etc. The sweetener comprises saccharin, dipotassium glycyrrhizinate, and sweet stevia. Acidulants include citric acid, malic acid, ascorbic acid, fumaric acid, and the like. Flavoring agents include 1-menthol, sodium chloride, sucrose, and the like. The pH regulator includes citrate, phosphate, carbonate, acetate, etc. The cosolvent comprises cyclodextrin, arginine, lysine, triaminomethane, etc. The colorant comprises ferric oxide yellow, ferric oxide, sodium copper chlorophyllin, etc. Flavoring agents include orange oil, lemon oil, peppermint oil, eucalyptus oil, and the like.

The tablets of the invention may be prepared according to conventional methods in the manufacture of tablets, for example, by: i) preparing a mixture comprising taurine and allopurinol, and one or more additives selected from the group consisting of excipients, disintegrants, lubricants, binders, plasticizers, coating agents, deflocculants, solubilizers, sweeteners, acidifiers, flavors, pH adjusters, co-solvents, colorants, and flavoring agents, and then ii) compression-molding the mixture obtained in i) above.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline. Examples of the nonaqueous solvent include vegetable oils such as propylene glycol, polyethylene glycol, and olive oil, alcohols such as ethanol, and tween 80. The preparation may also contain isotonic agent, antiseptic, wetting agent, emulsifier, dispersant, stabilizer, or dissolving adjuvant. For example, it may be sterilized by filtration through a filter that retains bacteria, by addition of a bactericide, or by irradiation. Alternatively, the composition may be prepared as a sterile solid, and may be used after being dissolved or suspended in sterile water or a sterile solvent for injection before use.

As the external preparations, ointments, plasters, creams, gels, patches, sprays, lotions, eye drops, eye ointments and the like are included. Such external preparations include conventional ointment bases, lotion bases, aqueous or non-aqueous liquid preparations, suspensions, emulsions and the like. Examples of the ointment base or lotion base include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, and sorbitan sesquioleate.

The transmucosal agents such as inhalants and nasal agents can be used in a solid, liquid or semisolid state, and can be prepared by a conventionally known method. For example, a known excipient, a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer, a thickener, or the like may be added as appropriate. Suitable devices for inhalation or insufflation may be used for administration. Alternatively, administration may be by pressurized aerosol spray or the like.

In the case of oral administration, the dose is preferably about 0.01 to 100mg/kg, preferably 0.1 to 10mg/kg, per body weight for 1 day, and the dose is administered once or in 2 to 4 divided doses. The dose is appropriately selected depending on the condition, age, sex, and the like.

The pharmaceutical composition of the present invention may be used in combination with other agents for treating or preventing hyperuricemia or a complication of hyperuricemia. When used in combination, they may be administered simultaneously, or separately and continuously, or at desired time intervals.

A third aspect of the present invention relates to the use of the pharmaceutical composition of the second aspect described above for preventing or treating hyperuricemia or a complication of hyperuricemia.

Elevated blood uric acid may lead to the development of complications such as gouty arthritis, gouty nephropathy, and atherosclerosis. The pharmaceutical composition disclosed by the invention is particularly effective in improving hyperuricemia atherosclerosis and reducing the risk of cardiovascular diseases caused by hyperuricemia.

Examples

The present invention will be further explained or illustrated by the following examples, which should not be construed as limiting the scope of the present invention.

It should be noted that various reagents and the like used in the following examples are known in the art and are commercially available.

Grouping experimental animals and preparing medicine

The male APOE mice were randomly divided into a blank group, a model group, an allopurinol group, a taurine group, an allopurinol + taurine combination administration group, and 12 mice per group.

Preparing a molding agent: potassium oxonate (1.4g) and adenine (0.525g) were mixed, and 7g of gum Arabic powder was added thereto, followed by grinding and suspension in 140ml of ultrapure water.

Administration and material taking of experimental animal

The administration was carried out by gavage at 9-10 am every day, and the aqueous suspension solution was administered to each administration group, and the molding agent was administered to each group after 1h except for the blank group which was administered with the same amount of aqueous solution. The administration volumes were 10 ml/kg.

After 90 days of continuous administration, about 300. mu.l of blood was collected from orbital venous plexus of mice, and after one hour of standing, the blood sample was centrifuged (4 ℃, 5000g, 10min), and plasma was aspirated and stored at-20 ℃. Abdominal cavity injection of 15% Avermen anesthesia (0.33ml/20g), dissection, complete extraction of aorta from mouse body and oil red O staining, observation and photography under Leica body type microscope, comparison of aortic plaque formation area size and statistics of it.

Detection of uric acid content in blood plasma

Mu.l of the sample was added to 270. mu.l of 0.3M perchloric acid, vortexed, mixed well, ice-cooled for 30min, and centrifuged (4 ℃, 10000g, 10 min). The supernatant was aspirated into 200. mu.l, 50. mu.l of 0.8M disodium hydrogen phosphate was added thereto, mixed well, and centrifuged (4 ℃, 10000g, 10 min). And sucking 20 mu l of supernatant, adding 180 mu l of acetonitrile, mixing uniformly, centrifuging (4 ℃, 14000g and 10min), and taking the supernatant as UPLC test solution. The uric acid content in plasma and urine was determined by literature methods.

UPLC analysis conditions were as follows:

a chromatographic column: ACQUITY UPLC BEH Amide (1.7 μm, 2.1X 50mm)

Mobile phase: 0.1% aqueous acetic acid/acetonitrile 10/90, v/v

Flow rate: 0.3ml/min

Column temperature: 30 deg.C

Detection wavelength: 285nm

Sample introduction amount: 10 μ l

Statistical treatment

The experimental results were analyzed by SPSS 20.0 statistical software, and the data were measured as mean. + -. standard deviation

Sample comparisons were performed using One-way ANOVA (One-way ANOVA) with a test level α of 0.05.

Results of the experiment

TABLE 1 Effect on serum uric acid levels after 3 months of administration

Group of	Dosage to be administered	Serum uric acid levels (μmol/L)
			Blank group	-	93.1±4.3**
Model set	-	187.2±9.7
			Taurine	400mg/kg	195.8±10.2
Allopurinol	25mg/kg	133.2±5.6**
			Taurine + allopurinol	400+25mg/kg	114.3±4.1**▽
Taurine + allopurinol	125+25mg/kg	173.3±6.2

Note: p <0.01, as compared to model group; v means P <0.05 compared to the allopurinol group

The results in table 1 show that the serum uric acid level in the model group is increased about 1-fold compared to the blank group (i.e., the normal mouse group), indicating that an animal model of hyperuricemia is formed.

When the taurine 400mg/kg is continuously administrated for 90 days, compared with a model group, the serum uric acid has no obvious change, which indicates that the independent administration of the taurine has no influence on the serum uric acid level.

Allopurinol 25mg/kg is continuously administrated for 90 days, and compared with a model group, the serum uric acid is obviously reduced, which shows that allopurinol has the function of reducing the serum uric acid level of an experimental animal with hyperuricemia.

The combined administration of 400mg/kg of taurine and 25mg/kg of allopurinol is adopted, and although the single administration of taurine has no obvious influence on serum uric acid, the combined administration further reduces the serum uric acid level compared with the single administration group of allopurinol, and has obvious difference. Therefore, under the condition of coexistence of allopurinol, taurine synergistically participates in regulation of uric acid metabolism, and the regulation effect of blood uric acid is enhanced.

TABLE 2 Effect on aortic plaque after 3 months of administration

Group of	Dosage to be administered	Plaque area/total area
			Blank group	-	6.7±0.5％**
Model set	-	13.8±0.9％
			Taurine	400mg/kg	11.0±0.4％*
Allopurinol	25mg/kg	15.2±1.7％
			Taurine + allopurinol	400+25mg/kg	8.7±0.6％**▽
Taurine + allopurinol	125+25mg/kg	12.6±1.5

Note: p <0.05 compared to model group; p <0.01, as compared to model group; v means compared to the taurine group, P <0.05

The results in table 2 show that, compared to the blank group, the aorta developed large area plaques after 3 months of molding, indicating that a hyperuricemic atherosclerotic model developed.

When taurine 400mg/kg is continuously administrated for 90 days, compared with a model group, the plaque area is obviously reduced.

Allopurinol 25mg/kg was administered continuously for 90 days, and had no effect of improving plaque formation as compared with the model group.

By adopting the combined administration of 400mg/kg of taurine and 25mg/kg of allopurinol, although the administration of allopurinol alone has no obvious influence on the plaque area, the plaque area is further reduced after the combined administration compared with the administration of taurine alone, and the obvious difference is achieved. Therefore, under the condition of coexistence of allopurinol, taurine is synergistically involved in regulating uric acid to cause arterial plaque formation, and the risk of cardiovascular diseases caused by high uric acid is reduced.

Claims (5)

1. A composition comprises taurine and allopurinol as main components, wherein the content ratio of the taurine to the allopurinol is 16:1 to 10:1 by mass ratio.

2. A pharmaceutical composition comprises taurine and allopurinol as main components, and a pharmaceutically acceptable additive, wherein the content ratio of the taurine to the allopurinol is 16:1 to 10:1 by mass ratio.

3. The pharmaceutical composition according to claim 2, which is used in the form of any one of tablets, pills, capsules and granules.

4. Use of the composition of claim 1 in the manufacture of a medicament for preventing or treating hyperuricemia or a complication of hyperuricemia.

5. The use of claim 4, wherein the complication of hyperuricemia comprises atherosclerosis.